Benchmarking whole exome sequencing in the German network for personalized medicine.
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Menzel Michael, Martis-Thiele Mihaela, Goldschmid Hannah, Ott Alexander, Romanovsky Eva, Siemanowski-Hrach Janna, Seillier Lancelot, Brüchle Nadina Ortiz, Maurer Angela, Lehmann Kjong-Van, Begemann Matthias, Elbracht Miriam, Meyer Robert, Dintner Sebastian, Claus Rainer, Meier-Kolthoff Jan P, Blanc Eric, Möbs Markus, Joosten Maria, Benary Manuela, Basitta Patrick, Hölscher Florian, Tischler Verena, Groß Thomas, Kutz Oliver, Prause Rebecca, William Doreen, Horny Kai, Goering Wolfgang, Sivalingam Sugirthan, Borkhardt Arndt, Blank Cornelia, Junk Stefanie V, Yasin Layal, Moskalev Evgeny A, Carta Maria Giulia, Ferrazzi Fulvia, Tögel Lars, Wolter Steffen, Adam Eugen, Matysiak Uta, Rosenthal Tessa, Dönitz Jürgen, Lehmann Ulrich, Schmidt Gunnar, Bartels Stephan, Hofmann Winfried, Hirsch Steffen, Dikow Nicola, Göbel Kirsten, Banan Rouzbeh, Hamelmann Stefan, Fink Annette, Ball Markus, Neumann Olaf, Rehker Jan, Kloth Michael, Murtagh Justin, Hartmann Nils, Jurmeister Phillip, Mock Andreas, Kumbrink Jörg, Jung Andreas, Mayr Eva-Maria, Jacob Anne, Trautmann Marcel, Kirmse Santina, Falkenberg Kim, Ruckert Christian, Hirsch Daniela, Immel Alexander, Dietmaier Wolfgang, Haack Tobias, Marienfeld Ralf, Fürstberger Axel, Niewöhner Jakob, Gerstenmaier Uwe, Eberhardt Timo, Greif Philipp A, Appenzeller Silke, Maurus Katja, Doll Julia, Jelting Yvonne, Jonigk Danny, Märkl Bruno, Beule Dieter, Horst David, Wulf Anna-Lena, Aust Daniela, Werner Martin, Reuter-Jessen Kirsten, Ströbel Philipp, Auber Bernd, Sahm Felix, Merkelbach-Bruse Sabine, Siebolts Udo, Roth Wilfried, Lassmann Silke, Klauschen Frederick, Gaisa Nadine T, Weichert Wilko, Evert Matthias, Armeanu-Ebinger Sorin, Ossowski Stephan, Schroeder Christopher, Schaaf Christian P, Malek Nisar, Schirmacher Peter, Kazdal Daniel, Pfarr Nicole, Budczies Jan, Stenzinger Albrecht
Аннотация
METHODS: To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics. Somatic and germline variants, copy-number alterations (CNAs), and complex biomarkers were investigated. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. The raw data were collected and re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability.
RESULTS: The mean positive percentage agreement (PPA) of somatic variant calling was 76 % while the positive predictive value (PPV) was 89 % in relation to a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88 % for all and 97 % for the clinically relevant variants. CNA calls were concordant for 82 % of genomic regions. Homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94 %, 93 %, and 93 % of calls, respectively. Variability of CNAs and complex biomarkers did not decrease considerably after harmonization of the bioinformatic processing and was hence attributed mainly to wet-lab differences.
CONCLUSION: Continuous optimization of bioinformatic workflows and participating in round robin tests are recommended.